Nitric oxide is an important inter and intra-cellular messenger which has been implicated in the pathogenesis of septic shock. Inhibition of nitric oxide synthase is under investigation as a treatment for hypotension in septic shock. In addition to the vasodilating effect of nitric oxide on vascular smooth muscle, nitric oxide also has effects on platelets and immune cells. In this investigation, we are examining the role of the nitric oxide pathway as a modulator of immune cell function. We have found that nitric oxide regulates cytokine production by human phagocytic cells. (J Immunol, 1994). Recent work has focused on determining whether human immune cells actually produce nitric oxide and if so under what conditions, and on defining nitric oxide dependent interactions between the endothelium and phagocytic cells. Data from this project suggest that human neutrophils do not make nitric oxide under a variety of conditions (J Immunol 1994, in press). However, nitric oxide may play an important role in the interaction between neutrophils and other cells including macrophages, endothelium and bronchial epithelial cells. Currently, we are attempting to make appropriate vectors to transfect nitric oxide synthase into human phagocytic cell lines. If successful, we will examine the effect of nitric oxide production in these cells on function (chemotaxis, superoxide production, cytokine release) and resistance to infection.